Journal of Bronchology & Interventional Pulmonology:
Ectopic adrenocorticotropic hormone secretion is responsible for 12% to 17% of all cases of the Cushing syndrome. One of the most commonly described causes of ectopic adrenocorticotropic hormone secretion is small cell carcinoma of the lung. A rare cause includes a functioning neuroendocrine tumor traditionally known as carcinoids that account for 5% of all mediastinal tumors. To our knowledge, all reported cases of mediastinal carcinoids are thymic in origin and only a minority of those is functional. We present a male patient with hypertension, obstructive sleep apnea, and acid-base disorder, in whom further investigation revealed an anterior mediastinal mass and Cushing syndrome.
*Division of Pulmonary and Critical Care Medicine
†Division of Pulmonary and Critical Care Medicine
Departments of ‡Internal Medicine
§Pathology, Bronx Lebanon Hospital Center, Bronx, NY
T.V. and K.B. wrote draft of the manuscript; G.D.-F. and S.V. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. M.N. has been involved in obtaining and revising pathological images.
Disclosure: There is no conflict of interest or other disclosures.
Reprints: Gilda Diaz-Fuentes, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457 (e-mail: firstname.lastname@example.org).
Received May 24, 2013
Accepted February 17, 2014
Anterior mediastinal masses have diverse etiology, which includes congenital, inflammatory, or neoplastic conditions.1 Anterior mediastinal masses account for 50% of mediastinal tumors with masses of thymic origin being the most common. Masses of thymic origin include thymomas, thymic carcinomas and cysts, and primary neuroendocrine tumors of thymus. Primary thymic neuroendocrine carcinomas (thymic NEC), previously called thymic carcinoids, account for 5% of tumors of thymic origin.2 Approximately 50% of patients have endocrine abnormalities, most commonly Cushing syndrome, because of ectopic adrenocorticotropin hormone production or multiple endocrine neoplasia (MEN) syndrome.3 Sleep disturbances have been associated with Cushing syndrome, but there are no reports of severe obstructive sleep apnea (OSA) in patients with Cushing syndrome secondary to thymic NEC.4,5 We report a patient with thymic NEC who presented with uncontrolled hypertension and symptoms of OSA and features of Cushing syndrome.
A 57-year-old man presented with complaint of diffuse chest pain of 5 days duration associated with nonproductive cough and shortness of breath. His medical history was significant for hypertension, obesity (body mass index, 39), and recently diagnosed severe OSA. Review of systems was significant for weight gain of 20 pounds, fatigue, bilateral lower extremity weakness, and erectile dysfunction for the past 2 to 3 months. Pertinent positives on his examination included an elevated blood pressure of 145/98 mm Hg, purple striae over the lower abdominal wall, and bilateral hydrocele. The chest radiograph on admission revealed anterior mediastinal mass (Fig. 1).
Significant laboratory data on presentation included a pH of 7.5, serum bicarbonate level of 33 mEq/L, and potassium level of 2.2 mEq/L. He was admitted to the intensive care unit. Despite continued potassium replacement he remained hypokalemic. Urine chemistry was significant for an elevated urine potassium level of 40 mEq/L with transtubular potassium gradient of 12.5, which confirmed renal potassium loss. His urine chloride level of 135 mEq/L confirmed chloride-resistant metabolic alkalosis. The constellations of refractory hypokalemia and chloride-resistant metabolic alkalosis with difficult to control hypertension were highly suggestive of hypercortisolism.
The patient was investigated for cortisol excess. Serum cortisol level was 53.1 ug/dL and adrenocorticotropic hormone (ACTH) level was 139.5 pg/mL, which was consistent with corticotrophin-dependent hypercortisolism. A low-dose and high-dose dexamethasone suppression test showed failure of suppression of serum cortisol level. A provisional diagnosis of Cushing syndrome secondary to ectopic ACTH secretion was made and work-up was initiated to locate the source of ectopic ACTH secretion. Computed tomography scan of the head revealed no gross pituitary neoplasm. Chest and abdominal computed tomography showed a 5.2×4.6 cm anterior mediastinal mass, bilateral adrenal hyperplasia, and mediastinal and abdominal lipomatosis (Fig. 2).
The anterior mediastinal mass was considered to be the source of ectopic ACTH secretion and he underwent a thoracotomy with modified Chamberlain procedure for resection. The mass was resected in total and pathologic analysis revealed a moderately differentiated neuroendocrine tumor, an atypical carcinoid (Fig. 3). However, no thymic tissue was identified. Immunohistochemical stains were consistent with neuroendocrine tumor and ATCH staining was positive (Fig. 4).
Postoperatively, patient did well. His electrolytes normalized and serum cortisol and ACTH levels decreased. At follow-up his blood pressure was well controlled and symptoms of OSA had totally resolved. A repeated sleep study conducted 6 months later showed a marked reduction in the apnea/hypopnea index from 62 to 7.2. A follow-up positron emission tomography scan 1 year postoperatively revealed no evidence of recurrence.
Neuroendocrine tumors, previously called as carcinoid tumors, are rare tumors, which were first described in 1888 in the ileum. Gastrointestinal tract involvement accounts for the majority of these tumors and usually present as carcinoid syndrome.6 Respiratory tract account for 25% of these neoplasms and originate from bronchi. Primary mediastinal NEC are rare tumors first described by Rosai and Higa in 1972.7 They originate from thymus or from paraganglionic structures within the mediastinum, or they may be the result of neoplastic transformation in misplaced embryonal rests within the mediastinum.8 Thymic NEC account for all of these tumors in the anterior-superior mediastinum.
Thymic NEC is predominantly seen in the anterior mediastinum. It is 3 to 4 times more common in men and affects the age groups between 40 to 60 years.3,9,10 Patients are usually asymptomatic or have nonspecific pulmonary symptoms. Symptoms can be related to endocrinopathies or rarely because of metastatic disease. 20% to 50% of thymic NEC shows evidence of endocrinopathy with Cushing syndrome being the commonest, due to ectopic ACTH secretion.3,10 Other reported endocrinopathies include MEN type I and MEN type II. Definitive treatment is surgical resection. Thymic NEC is much more aggressive than the neuroendocrine tumors originating in other locations. Survival is dependent of the histologic grade of tumor with a 5-year disease-free survival of 50% for well-differentiated tumors, 20% for moderately differentiated, and 0% for poorly differentiated tumors.10 Other factors influencing mortality include presence of endocrinopathy. Management options for patients with advanced disease are radiation and adjuvant chemotherapy, but the outcomes, side effects, and effectiveness of these are not clear at this time.
Neuropsychiatric features of Cushing syndrome include insomnia, fatigue, and a multitude of psychiatric syndromes, including frank psychosis and major depression. OSA has been described in Cushing disease and syndrome. Shipley and colleagues demonstrated sleep apnea in 11 of 22 patients with Cushing disease. Of these, 18% demonstrated moderate OSA with apnea-hypopnea index of >17.5 events/h.5 Weight gain is a common feature of Cushing syndrome with centripetal fat deposition. The peculiar distribution of adipose tissue readily distinguishes it from simple obesity. Fat accumulates in the face, supraclavicular areas, parapharyngeal regions, peritoneum, and mediastinum. This weight gain and fat accumulation in the oropharynx explain the OSA seen in this group of patients. It is also well known that glucocorticoid excess can cause centripetal obesity as well as mediastinal lipomatosis, which were present in our patient. Surgical resection of the tumor and cure may explain the resolution of OSA at 6 months in our patient.
Pathologic examination of the tumor did not identify thymic tissue. We can only assume that this tumor originated from the thymus and replaced it completely. Although speculative, we cannot exclude a nonthymic origin for this neuroendocrine tumor in the anterior mediastinum.
Our case is interesting because of many atypical features seen in this rather uncommon neoplasm. This patient had severe OSA, difficult to control hypertension, and developed severe resistant hypokalemia and metabolic alkalosis requiring intensive care. The finding of an anterior mediastinal neuroendocrine carcinoma unified the subspecialties of pulmonary, critical care, and sleep medicine. In addition, no thymic tissue was seen in the pathologic specimen. To the best of our knowledge this is the first report of presumed thymic NEC presenting as OSA.
Hypertension and OSA are common comorbidities encountered in our patients, with OSA being a rare manifestation of thymic NEC. Thymic NEC should be included in the differential diagnosis in patients presenting with OSA and manifestations of Cushing syndrome. In addition, a careful review of available imaging needs should be performed to identify early abnormalities. There patient are usually seen by a wide spectrum of physician and health care providers, so awareness of this association is recommended.
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Keywords:© 2014 by Lippincott Williams & Wilkins.
neuroendocrine tumor; OSA; Cushing syndrome; hypokalemia